Background: Women who were treated for a pediatric cancer with therapeutic radiation involving developing breast tissue have a significantly increased risk of developing breast cancer at a young age. By age 45, the cumulative incidence of breast cancer in survivors of childhood cancer treated with chest or mantle radiation therapy has been found to range from approximately 13% to 20%. (1-3) Estimates of the absolute excess risk of breast cancer range from 18.6 to 79.0 per 10,000 person-years. (1-5) Breast cancer in this population is associated with significant morbidity, mortality, and a diminished quality of life. Onset of breast cancer in survivors of a childhood cancer has been noted as early as eight years post radiation, with a median age at diagnosis of 35 years and a median interval from radiation of about 15 years. (1) The pathologic features and prognosis for Hodgkin’s lymphoma survivors with breast cancer are similar to the general population. Likewise 5-year survival rates are strongly associated with stage of disease at the time of diagnosis. While previous studies suggest that management of advanced stage breast cancer may be restricted by previous therapy, early-stage breast cancer remains highly curable. Partly for these reasons, multiple expert panels, including the Children’s Oncology Group and the American Cancer Society, have issued guidelines recommending annual screening of this high risk group. (6, 7) However, there is substantial variation between the different guidelines reflecting limited scientific evidence on some significant issues. A key concern is that the different guidelines target somewhat different populations for screening. This discrepancy highlights the need to better understand breast cancer risk modifiers in this population. Factors that are potentially readily available in clinical practice, such as the radiation field and dose found in medical charts and radiation records, are crucial for informing and refining screening recommendations and for counseling patients about preventive strategies, including but not limited to screening.

Methods: Radiation records of 1221 female participants in the Childhood Cancer Survivor Study (CCSS) were reviewed. Participants were diagnosed with their primary cancer before the age of 21 from 1970 through 1986 at one of 26 participating institutions and survived five or more years after their diagnosis. CCSS participants included in this analysis had to have been treated with radiation involving breast tissue. We excluded those participants whose only field of radiation near the chest was spinal radiation. The risk of breast cancer was estimated non-parametrically treating death as a competing risk in a delayed entry framework. The US population incidence of breast cancer was estimated using age-specific rates from the Surveillance, Epidemiology, and End Results (SEER) registries, weighted to account for the calendar year in which members of the CCSS cohort were at risk of BC.

Results: Childhood cancer diagnoses represented in this sub-cohort are Hodgkin’s lymphoma (n=663, 54%), Wilms tumor (n=143, 12%), leukemia (n=108, 9%), non-Hodgkin’s lymphoma (n=88, 7%), neuroblastoma (n=83, 6%), bone cancer (n=70, 6%), soft tissue sarcoma (n=57, 5%), and tumors of the central nervous system (CNS) (n=9, 1%). The median age at diagnosis was 12 years (range 0-20 years). The median duration of follow-up was 25 years (range 5-39 years). There was a wide degree of variation in the radiation fields used to treat these childhood cancer survivors. We categorized the fields of radiation as follows: mantle field (n=594 (48%), median dose = 3960 cGy), mediastinal/involved field radiation therapy (n= 213 (17%), median dose = 2880 cGy), whole lung (n=130 (11%), median dose = 1473 cGy), chest field without axilla (n=99 (8%), median dose = 3330 cGy), total body irradiation (TBI) (n=107 (9%), median dose = 1200 cGy), posterior chest field (n=49 (4%), median dose = 3500 cGy), high abdominal field (n=475 (39%), median dose = 3000 cGy). Four hundred sixty nine women (38%) were treated with more than one field of radiation. Ninety six (8%) women had a boost to their primary field Of the 1221 women, 175 have been diagnosed with breast cancer. Breast cancer was diagnosed after a median of 23 years following the pediatric cancer (range 7-38 years) at a median age of 38 years (range 24-53). The overall cumulative incidence of breast cancer was 11% by age 40 (95% CI: 9%-13%) and 24% by age 50 (95% CI: 20-28%). While breast cancer is most commonly thought of as a sequela of the mid- to high-dose mantle field radiation that was used to treat Hodgkin’s lymphoma, our data strongly suggest that subsequent breast cancer is not restricted to only these childhood cancer survivors. For CCSS participants treated with only mantle field radiation (and no other radiation field near the chest), the cumulative incidence of breast cancer by age 40 is 14% (95% CI: 10%-19%). In comparison, the cumulative incidence by age 40 is 12% (95% CI: 3%-27%) for participants treated with only whole lung radiation and 7% (95% CI: 2%-13%) for participants treated with only mediastinal/involved field radiation. These estimates are in contrast to a breast cancer incidence of 1% by age 40 in the general US population. The small numbers of participants treated with other fields of radiation and who are later diagnosed with breast cancer in these subgroups (chest field only: n=71, 3 with breast cancer; TBI only: n=107, 2 with breast cancer; posterior chest only: n=39, 1 with breast cancer; abdominal field only: n=74, 1 with breast cancer) prohibit us from estimating incidence separately for them. Similarly, subgroup numbers are too small to permit reliable estimation of breast cancer incidence by age 50. The addition of a second field of radiation does not appear to appreciably increase the risk of breast cancer. Looking at women who were treated with mantle field radiation either alone or in combination with another field of radiation therapy, where the median dose of the additional field(s) was 3500 cGy, the cumulative incidence by age 40 was 15% (95% CI: 11%-18%), an increase of 1% over the estimated incidence associated the mantle field alone. Likewise, including women who were treated with whole lung radiation together with at least one other field of radiation increases our estimate of the incidence by age 40 by 1% to 13% (95% CI: 6%-24%). For women treated with mediastinal/involved field radiation therapy, including those who were treated with additional field(s) results in an estimated incidence by age 40 of 5% (95% CI: 3%-14%), a drop of 2% relative to the incidence reported above.

Conclusions: There is considerable variability in the fields and doses of therapeutic radiation that may expose developing breast tissue to ionizing radiation. A substantially elevated risk of breast cancer is not limited to those pediatric cancer survivors treated with high dose mantle field radiation. Survivors of childhood cancers other than Hodgkin’s lymphoma who were treated with other fields of radiation at potentially lower doses also appear to have an increased risk of breast cancer.